Azo amino acids derivatives

ABSTRACT

The present invention relates to azo amino acid derivatives for treating or preventing neuronal damage associated with neurological diseases. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuing application of co-pending InternationalPatent Application PCT/US00/18416, filed Jul. 5, 2000, which claimspriority of U.S. provisional patent No. 60/142,569, filed Jul. 6, 1999.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to azo amino acid derivatives for treatingor preventing neuronal damage associated with neurological diseases. Theinvention also provides compositions comprising the compounds of thepresent invention and methods of utilizing those compositions fortreating or preventing neuronal damage.

BACKGROUND OF THE INVENTION

Neurological diseases are associated with the death of or injury toneuronal cells. Typical treatment of neurological diseases involvesdrugs capable of inhibiting neuronal cell death. A more recent approachinvolves the promotion of nerve regeneration by promoting neuronalgrowth.

Neuronal growth, which is critical for the survival of neurons, isstimulated in vitro by nerve growth factors (NGF). For example, GlialCell Line-Derived Neurotrophic Factor (GDNF) demonstrates neurotrophicactivity both, in vivo and in vitro, and is currently being investigatedfor the treatment of Parkinson's disease. Insulin and insulin-likegrowth factors have been shown to stimulate growth of neurites in ratpheochromocytoma PC12 cells and in cultured sympathetic and sensoryneurons [Recio-Pinto et al., J. Neurosci., 6, pp. 1211-1219 (1986)].Insulin and insulin-like growth factors also stimulate the regenerationof injured motor nerves in vivo and in vitro [Near et al., Proc. Natl.Acad. Sci., pp. 89, 11716-11720 (1992); and Edbladh et al., Brain Res.,641, pp. 76-82 (1994)]. Similarly, fibroblast growth factor (FGF)stimulates neural proliferation [D. Gospodarowicz et al., Cell Differ.,19, p. 1 (1986)] and growth [M. A. Walter et al., Lymphokine CytokineRes., 12, p. 135 (1993)].

There are, however, several disadvantages associated with the use ofnerve growth factors for treating neurological diseases. They do notreadily cross the blood-brain barrier. They are unstable in plasma andthey have poor drug delivery properties.

Recently, small molecules have been shown to stimulate neurite outgrowthin vivo. In individuals suffering from a neurological disease, thisstimulation of neuronal growth protects neurons from furtherdegeneration, and accelerates the regeneration of nerve cells. Forexample, estrogen has been shown to promote the growth of axons anddendrites, which are neurites sent out by nerve cells to communicatewith each other in a developing or injured adult brain [(C. DominiqueToran-Allerand et al., J. Steroid Biochem. Mol. Biol., 56, pp. 169-78(1996); and B. S. McEwen et al., Brain Res. Dev. Brain. Res., 87, pp.91-95 (1995)]. The progress of Alzheimer's disease is slowed in womenwho take estrogen. Estrogen is hypothesized to complement NGF and otherneurotrophins and thereby help neurons differentiate and survive.

Other target sites for the treatment of neurodegenerative disease arethe immunophilin class of proteins. Immunophilins are a family ofsoluble proteins that mediate the actions of immunosuppressant drugssuch as cyclosporin A, FK506 and rapamycin. Of particular interest isthe 12 kDa immunophilin, FK-506 binding protein (FKBP12). FKBP12 bindsFK-506 and rapamycin, leading to an inhibition of T-cell activation andproliferation. Interestingly, the mechanism of action of FK-506 andrapamycin are different. For a review, see, S. H. Solomon et al., NatureMed., 1, pp. 32-37 (1995). It has been reported that compounds with anaffinity for FKBP12 that inhibit that protein's rotomase activitypossess nerve growth stimulatory activity. [Lyons et al., Proc. Natl.Acad. Sci. USA, 91, pp. 3191-3195 (1994)]. Many of these such compoundsalso have immunosuppressive activity.

FK506 (Tacrolimus) has been demonstrated to act synergistically with NGFin stimulating neurite outgrowth in PC12 cells as well as sensoryganglia [Lyons et al. (1994)]. This compound has also been shown to beneuroprotective in focal cerebral ischemia [J. Sharkey and S. P.Butcher, Nature, 371, pp. 336-339 (1994)] and to increase the rate ofaxonal regeneration in injured sciatic nerve [B. Gold et al., J.Neurosci., 15, pp. 7509-16 (1995)].

The use of immunosuppressive compounds, however, has drawbacks in thatprolonged treatment with these compounds can cause nephrotoxicity [Koppet al., J. Am. Soc. Nephrol., 1, p. 162 (1991)], neurological deficits[P. C. DeGroen et al., N. Eng. J. Med., 317, p. 861 (1987)] and vascularhypertension [Kahan et al., N. Eng. J. Med., 321, p. 1725 (1989)].

More recently, sub-classes of FKBP binding compounds which inhibitrotomase activity, but which purportedly lack immunosuppressive functionhave been disclosed for use in stimulating nerve growth [see, U.S. Pat.No. 5,614,547; WO 96/40633; WO 96/40140; WO 97/16190; J. P. Steiner etal., Proc. Natl. Acad. Sci. USA, 94, pp. 2019-23 (1997); and G. S.Hamilton et al., Bioorg. Med. Chem. Lett., 7, pp. 1785-90 (1997)].

Stimulation of neural axons in nerve cells by piperidine derivatives isdescribed in WO 96/41609. Clinical use of the piperidine and pyrrolidinederivatives known so far for stimulating axonal growth has not beenpromising, as the compounds are unstable in plasma and do not pass theblood-brain barrier in adequate amounts.

Though a wide variety of neurological degenerative diseases may betreated by promoting repair of neuronal damage, there are relatively fewagents known to possess these properties. Thus, there remains a need fornew compounds and compositions that have the ability to either preventor treat neuronal damage associated with neuropathological diseases.

SUMMARY OF THE INVENTION

The present invention provides compounds having formula (I):

and pharmaceutically acceptable derivatives thereof, wherein:

X is O, S, NR¹ or C(R¹)₂

A, B and R¹ are independently E, (C₁-C₁₀)-straight or branched alkyl,(C₂-C₁₀)-straight or branched alkenyl or alkynyl, or (C₅-C₇)-cycloalkylor cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl oralkynyl are optionally and independently replaced with E,(C₅-C₇)-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the —CH₂—groups in said alkyl, alkenyl, or alkynyl groups is optionally andindependently replaced by —O—, —S—, —S(O)—, —S(O)₂—, ═N—, —N═ or—N(R³)—;

or B and R¹ are independently hydrogen;

wherein R³ is selected from hydrogen, (C₁-C₄)-straight or branchedalkyl, (C₃-C₄)-straight or branched alkenyl or alkynyl, or (C₁-C₄)bridging alkyl, wherein a bridge is formed between the nitrogen atom towhich said R³ is bound and any carbon atom of said alkyl, alkenyl oralkynyl to form a ring, and wherein said ring is optionally benzofused;

wherein E is a saturated, partially saturated or unsaturated, oraromatic monocyclic or bicyclic ring system, wherein each ring comprises5 to 7 ring atoms independently selected from C, N, O or S; and whereinno more than 4 ring atoms are selected from N, O or S;

wherein 1 to 4 hydrogen atoms in E are optionally and independentlyreplaced with halogen, hydroxyl, hydroxymethyl, nitro, SO₃H,trifluoromethyl, trifluoromethoxy, (C₁-C₆)-straight or branched alkyl,(C₂-C₆)-straight or branched alkenyl, O—[(C₁-C₆)-straight or branchedalkyl], O—[(C₃-C₆)-straight or branched alkenyl], (CH₂)_(n)—N(R⁴)(R⁵),(CH₂)_(n)—NH(R⁴)-(CH₂)_(n)—Z,(CH₂)_(n)—N(R⁴—(CH₂)_(n)—Z)(R⁵—(CH₂)_(n)—Z), (CH₂)_(n)—Z, O—(CH₂)_(n)—Z,(CH₂)_(n)—O—Z, S—(CH₂)_(n)—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH,C(O)O—[(C₁-C₆)-straight or branched alkyl], C(O)O—(CH₂)_(n)—Z orC(O)—N(R⁴)(R⁵);

wherein each of R⁴ and R⁵ are independently hydrogen, (C₁-C₆)-straightor branched alkyl, (C₃-C₅)-straight or branched alkenyl, or wherein R⁴and R⁵, when bound to the same nitrogen atom, are taken together withthe nitrogen atom to form a 5 or 6 membered ring, wherein said ringoptionally contains 1 to 3 additional heteroatoms independently selectedfrom N, O or S; wherein said alkyl, alkenyl or alkynyl groups in R₄ andR₅ are optionally substituted with Z.

each n is independently 0 to 4;

each Z is independently selected from a saturated, partially saturatedor unsaturated, monocyclic or bicyclic ring system, wherein each ringcomprises 5 to 7 ring atoms independently selected from C, N, O or S;and wherein no more than 4 ring atoms are selected from N, O or S;

wherein 1 to 4 hydrogen atoms in Z are optionally and independentlyreplaced with halo, hydroxy, nitro, cyano, C(O)OH, (C₁-C₃)-straight orbranched alkyl, O—(C₁-C₃)-straight or branched alkyl,C(O)O—[(C₁-C₃)-straight or branched alkyl], amino, NH[(C₁-C₃)-straightor branched alkyl], or N—[(C₁-C₃)-straight or branched alkyl]₂;

J and K are independently selected from hydrogen, (C₁-C₆)-straight orbranched alkyl, (C₂-C₆)-straight or branched alkenyl or alkynyl, orcyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenylor alkynyl is optionally and independently replaced with E;

provided that J and K are not simultaneously hydrogen;

wherein J and K are optionally and independently substituted with up to3 substituents selected from halogen, OH, O—(C₁-C₆)-alkyl,O—(CH₂)_(n)—Z, NO₂, C(O)OH, C(O)—O—(C₁-C₆)-alkyl, C(O)NR⁴R⁵, NR⁴R⁵ and(CH₂)_(n)—Z; or,

K taken together with one of J or R¹ forms a 5-7 membered saturated orunsaturated heterocyclic ring, optionally containing up to 3 additionalheteroatoms selected from O, N, S and S(O₂), wherein 1 to 4 hydrogenatoms in said heterocyclic ring are optionally and independentlyreplaced with (C₁-C₆)-straight or branched alkyl, (C₂-C₆)-straight orbranched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any —CH₂—group said heterocyclic ring is optionally and independently replaced by—O—, —S—, —S(O)—, —S(O₂)—, or —N(R³)—; and wherein said heterocyclicring is optionally fused with E;

G, when present, is —S(O)₂—, —C(O)—, —S(O)₂—Y—, —C(O)—Y—, —C(O)—C(O)—,or —C(O)—C(O)—Y—;

Y is oxygen, or N(R⁶);

wherein R⁶ is hydrogen, E, (C₁-C₆)-straight or branched alkyl,(C₃-C₆)-straight or branched alkenyl or alkynyl; or wherein R⁶ and D aretaken together with the atoms to which they are bound to form a 5 to 7membered ring system wherein said ring optionally contains 1 to 3additional heteroatoms independently selected from O, S, N, NH, SO, orSO₂; and wherein said ring is optionally benzofused;

D is hydrogen, (C₁-C₇)-straight or branched alkyl, (C₂-C₇)-straight orbranched alkenyl or alkynyl, (C₅-C₇)-cycloalkyl or cycloalkenyloptionally substituted with (C₁-C₆)-straight or branched alkyl or(C₂-C₇)-straight or branched alkenyl or alkynyl, [(C₁-C₇)-alkyl]-E,[(C₂-C₇)-alkenyl or alkynyl]-E, or E;

wherein 1 to 2 of the CH₂ groups of said alkyl, alkenyl or alkynylchains in D is optionally replaced by —O—, —S—, —S(O)—, —S(O₂)—, or—N(R³);

m is 0 to 3; and

x is 0 or 1;

provided that when J is hydrogen or G is selected from

—S(O)₂—, C(O)C(O)—, SO₂—Y, C(O)—Y, or C(O)C(O)—Y, wherein Y is O; then Dis not hydrogen.

In another embodiment, the invention provides pharmaceuticalcompositions comprising the compounds of formula (I). These compositionsmay be utilized in methods treating various neurological diseases whichare influenced by neuronal regeneration and axon growth or forstimulating neuronal regeneration in an ex vivo nerve cell. Examples ofsuch diseases include peripheral nerve destruction due to physicalinjury or diseases such as diabetes; physical injuries to the centralnervous system (e.g., brain or spinal cord); stroke; neurologicaldisturbances due to nerve degeneration, such as Parkinson's disease,Alzheimer's disease, and amylotrophic lateral sclerosis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds having formula (I):

and pharmaceutically acceptable derivatives thereof, wherein:

X is O, S, NR¹ or C(R¹)₂

A, B and R¹ are independently E, (C₁-C₁₀)-straight or branched alkyl,(C₂-C₁₀)-straight or branched alkenyl or alkynyl, or (C₅-C₇)-cycloalkylor cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl oralkynyl are optionally and independently replaced with E,(C₅-C₇)-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the —CH₂—groups in said alkyl, alkenyl, or alkynyl groups is optionally andindependently replaced by —O—, —S—, —S(O)—, —S(O)₂—, ═N—, —N═ or—N(R³)—;

or B and R¹ are independently hydrogen;

wherein R³ is selected from hydrogen, (C₁-C₄)-straight or branchedalkyl, (C₃-C₄)-straight or branched alkenyl or alkynyl, or (C₁-C₄)bridging alkyl, wherein a bridge is formed between the nitrogen atom towhich said R³ is bound and any carbon atom of said alkyl, alkenyl oralkynyl to form a ring, and wherein said ring is optionally benzofused;

wherein E is a saturated, partially saturated or unsaturated, oraromatic monocyclic or bicyclic ring system, wherein each ring comprises5 to 7 ring atoms independently selected from C, N, O or S; and whereinno more than 4 ring atoms are selected from N, O or S;

wherein 1 to 4 hydrogen atoms in E are optionally and independentlyreplaced with halogen, hydroxyl, hydroxymethyl, nitro, SO₃H,trifluoromethyl, trifluoromethoxy, (C₁-C₆)-straight or branched alkyl,(C₂-C₆)-straight or branched alkenyl, O—[(C₁-C₆)-straight or branchedalkyl], O—[(C₃-C₆)-straight or branched alkenyl], (CH₂)_(n)—N(R⁴)(R⁵),(CH₂)_(n)—NH(R⁴)—(CH₂)_(n)—Z,(CH₂)_(n)—N(R⁴—(CH₂)_(n)—Z)(R⁵—(CH₂)_(n)—Z), (CH₂)_(n)—Z, O—(CH₂)_(n)—Z,(CH₂)_(n)—O—Z, S—(CH₂)_(n)—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH,C(O)O—[(C₁-C₆)-straight or branched alkyl], C(O)O—(CH₂)_(n)—Z orC(O)—N(R⁴)(R⁵);

wherein each of R⁴ and R⁵ are independently hydrogen, (C₁-C₆)-straightor branched alkyl, (C₃-C₅)-straight or branched alkenyl, or wherein R⁴and R⁵, when bound to the same nitrogen atom, are taken together withthe nitrogen atom to form a 5 or 6 membered ring, wherein said ringoptionally contains 1 to 3 additional heteroatoms independently selectedfrom N, O or S; wherein said alkyl, alkenyl or alkynyl groups in R₄ andR₅ are optionally substituted with Z.

each n is independently 0 to 4;

each Z is independently selected from a saturated, partially saturatedor unsaturated, monocyclic or bicyclic ring system, wherein each ringcomprises 5 to 7 ring atoms independently selected from C, N, O or S;and wherein no more than 4 ring atoms are selected from N, O or S;

wherein 1 to 4 hydrogen atoms in Z are optionally and independentlyreplaced with halo, hydroxy, nitro, cyano, C(O)OH, (C₁-C₃)-straight orbranched alkyl, O—(C₁-C₃)-straight or branched alkyl,C(O)O—[(C₁-C₃)-straight or branched alkyl], amino, NH[(C₁-C₃)-straightor branched alkyl], or N—[(C₁-C₃)-straight or branched alkyl]₂;

J and K are independently selected from hydrogen, (C₁-C₆)-straight orbranched alkyl, (C₂-C₆)-straight or branched alkenyl or alkynyl, orcyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenylor alkynyl is optionally and independently replaced with E; providedthat J and K are not simultaneously hydrogen;

wherein J and K are optionally and independently substituted with up to3 substituents selected from halogen, OH, O—(C₁-C₆)-alkyl,O—(CH₂)_(n)—Z, NO₂, C(O)OH, C(O)—O—(C₁-C₆)-alkyl, C(O)NR⁴R⁵, NR⁴R⁵ and(CH₂)_(n)—Z; or,

K taken together with one of J or R¹ forms a 5-7 membered saturated orunsaturated heterocyclic ring, optionally containing up to 3 additionalheteroatoms selected from O, N, S and S(O₂), wherein 1 to 4 hydrogenatoms in said heterocyclic ring are optionally and independentlyreplaced with (C₁-C₆)-straight or branched alkyl, (C₂-C₆)-straight orbranched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any —CH₂—group said heterocyclic ring is optionally and independently replaced by—O—, —S—, —S(O)—, —S(O₂)—, or —N(R³)—; and wherein said heterocyclicring is optionally fused with E;

G, when present, is —S(O)₂—, —C(O)—, —S(O)₂—Y—, —C(O)—Y—, —C(O)—C(O)—,or —C(O)—C(O)—Y—;

Y is oxygen, or N(R⁶);

wherein R⁶ is hydrogen, E, (C₁-C₆)-straight or branched alkyl,(C₃-C₆)-straight or branched alkenyl or alkynyl; or wherein R⁶ and D aretaken together with the atoms to which they are bound to form a 5 to 7membered ring system wherein said ring optionally contains 1 to 3additional heteroatoms independently selected from O, S, N, NH, SO, orSO₂; and wherein said ring is optionally benzofused;

D is hydrogen, (C₁-C₇)-straight or branched alkyl, (C₂-C₇)-straight orbranched alkenyl or alkynyl, (C₅-C₇)-cycloalkyl or cycloalkenyloptionally substituted with (C₁-C₆)-straight or branched alkyl or(C₂-C₇)-straight or branched alkenyl or alkynyl, [(C₁-C₇)-alkyl]-E,[(C₂-C₇)-alkenyl or alkynyl]-E, or E;

wherein 1 to 2 of the CH₂ groups of said alkyl, alkenyl or alkynylchains in D is optionally replaced by —O—, —S—, —S(O)—, —S(O₂)—, or—N(R³);

m is 0 to 3; and

x is 0 or 1;

provided that when J is hydrogen or G is selected from

—S(O)₂—, C(O)C(O)—, SO₂—Y, C(O)—Y, or C(O)C(O)—Y,

wherein Y is O; then D is not hydrogen.

According to a preferred embodiment, each of A and B in formula (I) is(C1-C10) straight or branched alkyl, wherein 1-2 hydrogen atoms in saidalkyl are optionally substituted with E.

In another preferred embodiment, B is hydrogen.

According to a more preferred embodiment, each of A and B in formula (I)is —CH₂—CH₂—E or —CH₂—CH₂—CH₂—E.

According to another preferred embodiment, D in formula (I) is (C1-C7)straight or branched alkyl, E or [(C1-C6)-straight or branched alkyl]-E.

According to a more preferred embodiment, D is an aromatic monocyclic orbicyclic ring system, wherein each ring comprises 5-7 ring atomsindependently selected from C, N, O or S, and wherein no more than 4ring atoms are selected from N, O or S.

According to an even more preferred embodiment, D is phenyl or C₁-C₇straight or branched alkyl group.

According to another preferred embodiment, E in formula (I) is amonocyclic or bicyclic aromatic ring system, wherein said ring comprises5-7 ring atoms independently selected from C, N, O or S, and wherein 1to 4 ring atoms are independently selected from N, O or S.

Preferred embodiments of E include phenyl, napthyl, indenyl, azulenyl,fluorenyl; anthracenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,isothiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl,1,3,5-trazinyl, 1,3,5-trithianyl, benzo[b]furanyl, benzo[b]thiophenyl,purinyl, cinnolinyl, phthalazinyl, isoxazolyl, triazolyl, oxadiazolyl,pyrimidinyl, pyrazinyl, indolinyl, indolizinyl, isoindolyl,benzimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl,acridinyl, phnazinyl, phenothiazinyl, phenoxazinyl and benzothiazolyl,wherein E is optionally substituted as described above.

More preferred embodiments of E include phenyl, furyl, thienyl, pyridyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,triazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl,benzimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, andbenzothiazolyl, wherein E is optionally substituted as described above.

According to another preferred embodiment, J is H, methyl, ethyl orbenzyl; and

K is selected from (C₁-C₆)-straight or branched alkyl, (C₂-C₆)-straightor branched alkenyl 5 or alkynyl, or cyclohexylmethyl, wherein 1 to 2hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally andindependently replaced with E.

According to another preferred embodiment, J and K, taken together withthe nitrogen atom, form a 5-7 membered heterocyclic ring, optionallycontaining up to 3 additional heteroatoms selected from O, N, S andS(O₂), wherein 1 to 4 hydrogen atoms in said heterocyclic ring areoptionally and independently replaced with (C₁-C₆)-straight or branchedalkyl, (C₂-C₆)-straight or branched alkenyl or alkynyl, oxo, hydroxyl orZ; and wherein any —CH₂— group said heterocyclic ring is optionally andindependently replaced by —O—, —S—, —S(O)—, —S(O₂)—, or —N(R³)—; andwherein said heterocyclic ring is optionally fused with E.

According to another preferred embodiment, K and R1, taken together withthe nitrogen atom, form a 5-7 membered heterocyclic ring, optionallycontaining up to 3 additional heteroatoms selected from O, N, S andS(O₂), wherein 1 to 4 hydrogen atoms in said heterocyclic ring areoptionally and independently replaced with (C₁-C₆)-straight or branchedalkyl, (C₂-C₆)-straight or branched alkenyl or alkynyl, oxo, hydroxyl orZ; and wherein any —CH₂— group said heterocyclic ring is optionally andindependently replaced by —O—, —S—, —S(O)—, —S(O₂)—, or —N(R³)—; andwherein said heterocyclic ring is optionally fused with E.

The compounds of formula (I) may be stereoisomers, geometric isomers orstable tautomers. The invention envisions all possible isomers, such asE and Z isomers, S and R enantiomers, diastereoisomers, racemates, andmixtures of those. It is preferred that the substituent in the 2position have the S configuration.

The compounds of the present invention may be readily prepared usingknown synthetic methods. For example, compounds of formula (I) may beprepared as shown below in Scheme I:

a=J—CHO and NaCNBH₃ b=D—Cl or D—Br and K₂CO₃ when x=0; D—G—Cl anddiisopropylethylamine when x=1; c=HCl/EtOAc or trifluoroaceticacid/CH₂Cl₂; K—CHO and NaCNBH₃; e=COCl₂ followed by the addition of theamine or alcohol of —X—(CH₂)_(m)—CH(A)(B).

One of skill in the art would be well aware of analogous syntheticmethods to prepare the compounds of the present invention.

According to another embodiment, this invention provides compositionscomprising a compound of formula. (I) and a pharmaceutically acceptablecarrier.

Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxy methylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene block polymers, polyethylene glycol andwool fat.

In another embodiment, the composition of the present invention iscomprised of a compound of formula (I), a pharmaceutically acceptablecarrier, and a neurotrophic factor.

The term “neurotrophic factor,” as used herein, refers to compoundswhich are capable of stimulating growth or proliferation of nervoustissue. Numerous neurotrophic factors have been identified in the artand any of those factors may be utilized in the compositions of thisinvention. These neurotrophic factors include, but are not limited to,nerve growth factor (NGF), insulin-like growth factor (IGF-1) and itsactive truncated derivatives such as gIGF-1 and Des(1-3)IGF-I, acidicand basic fibroblast growth factor (aFGF and bFGF, respectively),platelet-derived growth factors (PDGF), brain-derived neurotrophicfactor (BDNF), ciliary neurotrophic factors (CNTF), glial cellline-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3)andneurotrophin 4/5 (NT-4/5). The most preferred neurotrophic factor in thecompositions of this invention is NGF.

As used herein, the described compounds used in the compositions andmethods of this invention, are defined to include pharmaceuticallyacceptable derivatives thereof. A “pharmaceutically acceptablederivative” denotes any pharmaceutically acceptable salt, ester, or saltof such ester, of a compound of this invention or any other compoundwhich, upon administration to a patient, is capable of providing(directly or indirectly) a compound of this invention, or a metaboliteor residue thereof, characterized by the ability to promote repair orprevent damage of neurons from disease or physical trauma.

If pharmaceutically acceptable salts of the described compounds areused, those salts are preferably derived from inorganic or organic acidsand bases. Included among such acid salts are the following: acetate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.Base salts include ammonium salts, alkali metal salts, such as sodiumand potassium salts, alkaline earth metal salts, such as calcium andmagnesium salts, salts with organic bases, such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth. Also, the basic nitrogen-containinggroups can be quaternized with such agents as lower alkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides and iodides;dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamylsulfates, long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides, such as benzyl andphenethyl bromides and others. Water or oil-soluble or dispersibleproducts are thereby obtained.

The described compounds utilized in the compositions and methods of thisinvention may also be modified by appending appropriate functionalitiesto enhance selective biological properties. Such modifications are knownin the art and include those which increase biological penetration intoa given biological system (e.g., blood, lymphatic system, centralnervous system), increase oral availability, increase solubility toallow administration by injection, alter metabolism and alter rate ofexcretion.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The compositions of this invention may be orally administered in anyorally acceptable dosage form including, but not limited to, capsules,tablets, aqueous suspensions or solutions. In the case of tablets fororal use, carriers which are commonly used include lactose and cornstarch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried corn starch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the compositions of this invention may be administered inthe form of suppositories for rectal administration. These can beprepared by mixing the agent with a suitable non-irritating excipientwhich is solid at room temperature but liquid at rectal temperature andtherefore will melt in the rectum to release the drug. Such materialsinclude cocoa butter, beeswax and polyethylene glycols.

The compositions of this invention may also be administered topically,especially when the target of treatment includes areas or organs readilyaccessible by topical application, including diseases of the eye, theskin, or the lower intestinal tract. Suitable topical formulations arereadily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the compositions may be formulated in asuitable ointment containing the active component suspended or dissolvedin one or more carriers. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, the compositions can be formulated in a suitable lotionor cream containing the active components suspended or dissolved in oneor more pharmaceutically acceptable carriers. Suitable carriers include,but are not limited to, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcoholand water.

For ophthalmic use, the compositions may be formulated as micronizedsuspensions in isotonic, pH adjusted sterile saline, or, preferably, assolutions in isotonic, pH adjusted sterile saline, either with ourwithout a preservative such as benzylalkonium chloride. Alternatively,for ophthalmic uses, the compositions may be formulated in an ointmentsuch as petrolatum.

The compositions of this invention may also be administered by nasalaerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of formulation and may be prepared assolutions in saline, employing benzyl alcohol or other suitablepreservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other conventional solubilizing or dispersingagents.

The amount of both a described compound and the optional neurotrophicfactor that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Preferably, the compositions shouldbe formulated so that a dosage of between 0.01-100 mg/kg body weight/dayof the described compound can be administered. If a neurotrophic factoris present in the composition, then a dosage of between 0.01 μg −100mg/kg body weight/day of the neurotrophic factor can be administered toa patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of active ingredients will also depend upon the particulardescribed compound and neurotrophic factor in the composition.

According to another embodiment, this invention provides methods forpromoting repair or preventing neuronal damage or neuronal degenerationin vivo or in an ex vivo nerve cell. Such methods comprise the step oftreating nerve cells with any of the compounds described above.Preferably, this method promotes repair or prevents neuronal damage in apatient, and the compound is formulated into a composition additionallycomprising a pharmaceutically acceptable carrier. The amount of thecompound utilized in these methods is between about 0.01 and 100 mg/kgbody weight/day.

According to an alternate embodiment, the method of promoting repair orpreventing neuronal damage comprises the additional step of treatingnerve cells with a neurotrophic factor, such as those contained in thecompositions of this invention. This embodiment includes administeringthe compound and the neurotrophic agent in a single dosage form or inseparate, multiple dosage forms. If separate dosage forms are utilized,they may be administered concurrently, consecutively or within less thanabout 5 hours of one another.

Preferably, the methods of this invention are used to stimulate axonalgrowth in nerve cells. The compounds are, therefore, suitable fortreating or preventing neuronal damage caused by a wide variety ofdiseases or physical traumas. These include, but are not limited to,Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease,Tourette's syndrome, stroke and ischemia associated with stroke, neuralparopathy, other neural degenerative diseases, motor neuron diseases,sciatic crush, spinal cord injuries and facial nerve crush.

In a particularly preferred embodiment of the invention, the method isused to treat a patient suffering from trigeminal neuralgia,glosspharyngeal neuralgia, Bell's Palsy, myasthenia gravis, musculardystrophy, muscle injury, progressive muscular atrophy, progressivebulbar inherited muscular atrophy, herniated, ruptured, or prolapsedinvertebrae disk syndrome's, cervical spondylosis, plexus disorders,thoracic outlet destruction syndromes, peripheral neuropathies, such asthose caused by lead, dapsone, ticks, or porphyria, other peripheralmyelin disorders, Alzheimer's disease, Gullain-Barre syndrome,Parkinson's disease and other Parkinsonian disorders, ALS, Tourette'ssyndrome, multiple sclerosis, other central myelin disorders, stroke andischemia associated with stroke, neural paropathy, other neuraldegenerative diseases, motor neuron diseases, sciatic crush, neuropathyassociated with diabetes, spinal cord injuries, facial nerve crush andother trauma, chemotherapy- and other medication-induced neuropathies,and Huntington's disease.

More preferably, the compositions of the present invention are used fortreating Parkinson's disease, amylotrophic lateral sclerosis,Alzheimer's disease, stroke, neuralgias, muscular atrophies, andGuillain-Barré syndrome.

For use of the compounds according to the invention as medications, theyare administered in the form of a preparation containing not only theactive ingredient but also carriers, auxiliary substances, and/oradditives suitable for enteric or parenteral administration.Administration can be oral or sublingual as a solid in the form ofcapsules or tablets, as a liquid in the form of solutions, suspensions,elixirs, aerosols or emulsions, or rectal in the form of suppositories,or in the form of solutions for injection which can be givensubcutaneously, intramuscularly, or intravenously, or which can be giventopically or intrathecally. Auxiliary substances for the desiredmedicinal formulation include the inert organic and inorganic carriersknown to those skilled in the art, such as water, gelatin, gum arabic,lactose, starches, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The medicinal formulations may also containpreservatives, stabilizers, wetting agents, emulsifiers, or salts tochange the osmotic pressure or as buffers.

Solutions or suspensions for injection are suitable for parenteraladministration, and especially aqueous solutions of the active compoundsin polyhydroxy-ethoxylated castor oil.

Surface-active auxiliary substances such as salts of gallic acid, animalor vegetable phospholipids, or mixtures of them, and liposomes or theircomponents, can be used as carrier systems.

The neurotrophic effect of the compounds of formula (I) of the presentinvention and their physiologically acceptable salts can be determinedby the methods of W. E. Lyons et al., Proc. Natl. Acad. Sci. USA, Vol.91, pp. 3191-3195 (1994) and W. E. Lyons et al., Proc. Natl. Acad. Sci.USA, Vol. 91, pages 3191-3195 (1994).

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

EXAMPLE 1 Compound 103-109

Compounds 103-109 have the following general formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 103

—CH₂CH₃— compound 104

—C(O)—CH₃— compound 105

—CH₂—Ph— compound 106

—C(O)—Ph— compound 107

—C(O)—O—CH₂—Ph— compound 108

—C(O)—C(O)—Ph— compound 109, wherein Ph is phenyl.

EXAMPLE 2 Compound 110-116

Compounds 110-116 have the following general formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 110

—CH₂CH₃— compound 111

—C(O)—CH₃— compound 112

—CH₂—Ph— compound 113

—C(O)—Ph— compound 114

—C(O)—O—CH₂—Ph— compound 115

—C(O)—C(O)—Ph— compound 116, wherein Ph is phenyl.

EXAMPLE 3 Compound 117-123

Compounds 117-123 have the following general formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 117

—CH₂CH₃— compound 118

—C(O)—CH₃— compound 119

—CH₂—Ph— compound 120

—C(O)—Ph— compound 121

—C(O)—O—CH₂—Ph— compound 122

—C(O)—C(O)—Ph— compound 123, wherein Ph is phenyl.

EXAMPLE 4 Compound 124-130

Compounds 124-130 have the following general formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 124

—CH₂CH₃— compound 125

—C(O)—CH₃— compound 126

—CH₂—Ph— compound 127

—C(O)—Ph— compound 128

—C(O)—O—CH₂—Ph— compound 129

—C(O)—C(O)—Ph— compound 130, wherein Ph is phenyl.

EXAMPLE 5

Compound 131-137

Compounds 131-137 have the following general formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 131

—CH₂CH₃— compound 132

—C(O)—CH₃— compound 133

—CH₂—Ph— compound 134

—C(O)—Ph— compound 135

—C(O)—O—CH₂—Ph— compound 136

—C(O)—C(O)—Ph— compound 137, wherein Ph is phenyl.

EXAMPLE 6 Compound 138-144

Compounds 138-144 have the following general formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 138

—CH₂CH₃— compound 139

—C(O)—CH₃— compound 140

—CH₂—Ph— compound 141

—C(O)—Ph— compound 142

—C(O)—O—CH₂—Ph— compound 143

—C(O)—C(O)—Ph— compound 144, wherein Ph is phenyl.

EXAMPLE 7 Compound 145-151

Compounds 145-151 have the following general formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 145

—CH₂CH₃— compound 146

—C(O)—CH₃— compound 147

—CH₂—Ph— compound 148

—C(O)—Ph— compound 149

—C(O)—O—CH₂—Ph— compound 150

—C(O)—C(O)—Ph— compound 151, wherein Ph is phenyl.

EXAMPLE 8 Compound 152-158

Compounds 152-158 have the following general formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 152

—CH₂CH₃— compound 153

—C(O)—CH₃— compound 154

—CH₂—Ph— compound 155

—C(O)—Ph— compound 156

—C(O)—O—CH₂—Ph— compound 157

—C(O)—C(O)—Ph— compound 158, wherein Ph is phenyl.

EXAMPLE 9 Compound 159-165

Compounds 159-165 have the following general formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 159

—CH₂CH₃— compound 160

—C(O)—CH₃— compound 161

—CH₂—Ph— compound 162

—C(O)—Ph— compound 163

—C(O)—O—CH₂—Ph— compound 164

—C(O)—C(O)—Ph— compound 165, wherein Ph is phenyl.

EXAMPLE 10 Compound 166-172

Compounds 166-172 have the following general formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 166

—CH₂CH₃— compound 167

—C(O)—CH₃— compound 168

—CH₂—Ph— compound 169

—C(O)—Ph— compound 170

—C(O)—O—CH₂—Ph— compound 171

—C(O)—C(O)—Ph— compound 172, wherein Ph is phenyl.

EXAMPLE 11 Compound 173-179

Compounds 173-179 are made according to scheme and have the followinggeneral formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 173

—CH₂CH₃— compound 174

—C(O)—CH₃— compound 175

—CH₂—Ph— compound 176

—C(O)—Ph— compound 177

—C(O)—O—CH₂—Ph— compound 178

—C(O)—C(O)—Ph— compound 179, wherein Ph is phenyl.

EXAMPLE 12 Compound 180-186

Compounds 180-186 are made according to scheme and have the followinggeneral formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 180

—CH₂CH₃— compound 181

—C(O)—CH₃— compound 182

—CH₂—Ph— compound 183

—C(O)—Ph— compound 184

—C(O)—O—CH₂—Ph— compound 185

—C(O)—C(O)—Ph— compound 186, wherein Ph is phenyl.

EXAMPLE 13 Compound 187-192

Compounds 180-186 are made according to scheme and have the followinggeneral formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 187

—CH₂CH₃— compound 188

—C(O)—CH₃— compound 189

—CH₂—Ph— compound 190

—C(O)—Ph— compound 191

—C(O)—O—CH₂—Ph— compound 192

—C(O)—C(O)—Ph— compound 193, wherein Ph is phenyl.

EXAMPLE 14 Compound 193-199

Compounds 180-186 are made according to scheme and have the followinggeneral formula:

wherein —(G)_(x)—D is as follows:

—CH₃— compound 193

—CH₂CH₃— compound 194

—C(O)—CH₃— compound 195

—CH₂—Ph— compound 196

—C(O)—Ph— compound 197

—C(O)—O—CH₂—Ph— compound 198

—C(O)—C(O)—Ph— compound 199, wherein Ph is phenyl.

While we have described a number of embodiments of this invention, it isapparent that our basic constructions may be altered to provide otherembodiments which utilize the products, processes and methods of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims, rather than by thespecific embodiments which have been presented by way of example.

What is claimed is:
 1. A compound having formula (I):

or a pharmaceutically acceptable salt thereof, wherein: one of A and Bis a (C₁-C₁₀)-straight or branched alkyl substituted with pyridine or a(C₂-C₁₀)-straight or branched alkenyl or alkynyl substituted withpyridine; and the other of A and B (C₁-C₁₀)-straight or branched alkylsubstituted with phenyl or a (C₂-C₁₀)-straight or branched alkenyl oralkynyl substituted with phenyl; X is NR¹; R¹ is E, (C₁-C₁₀)-straight orbranched alkyl, (C₂-C₁₀)-straight or branched alkenyl or alkynyl, or(C₅-C₇)-cycloalkyl or cycloalkenyl; wherein 1 or 2 hydrogen atoms insaid alkyl, alkenyl or alkynyl are optionally and independently replacedwith E, (C₅-C₇)-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the—CH₂— groups in said alkyl, alkenyl, or alkynyl groups is optionally andindependently replaced by —O—, —S—, —S(O)—, —S(O)₂—, ═N—, —N═ or—N(R³)—; or R¹ is hydrogen; wherein R³ is selected from hydrogen,(C₁-C₄)-straight or branched alkyl, (C₃-C₄)-straight or branched alkenylor alkynyl, or (C₁-C₄) bridging alkyl, wherein a bridge is formedbetween the nitrogen atom to which said R³ is bound and any carbon atomof said alkyl, alkenyl or alkynyl to form a ring, and wherein said ringis optionally benzofused; wherein E is a saturated, partially saturatedor unsaturated, or aromatic monocyclic or bicyclic ring system, whereineach ring comprises 5 to 7 ring atoms independently selected from C, N,O or S; and wherein no more than 4 ring atoms are selected from N, O orS; wherein 1 to 4 hydrogen atoms in E are optionally and independentlyreplaced with halogen, hydroxyl, hydroxymethyl, nitro, SO₃H,trifluoromethyl, trifluoromethoxy, (C₁-C₆)-straight or branched alkyl,(C₂-C₆)-straight or branched alkenyl, O—[(C₁-C₆)-straight or branchedalkyl], O—[(C₃-C₆)-straight or branched alkenyl], (CH₂)_(n)—N(R⁴)(R⁵),(CH₂)_(n)—NH(R⁴)—(CH₂)_(n)—Z,(CH₂)_(n)—N(R⁴—(CH₂)_(n)—Z)(R⁵—(CH₂)_(n)—Z), (CH₂)_(n)—Z, O—(CH₂)_(n)—Z,(CH₂)_(n)—O—Z, S—(CH₂)_(n)—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH,C(O)O—[(C₁-C₆)-straight or branched alkyl], C(O)O—(CH₂)_(n)—Z orC(O)—N(R⁴)(R⁵); wherein each of R⁴ and R⁵ are independently hydrogen,(C₁-C₆)-straight or branched alkyl, (C₃-C₅)-straight or branchedalkenyl, or wherein R⁴ and R⁵, when bound to the same nitrogen atom, aretaken together with the nitrogen atom to form a 5 or 6 membered ring,wherein said ring optionally contains 1 to 3 additional heteroatomsindependently selected from N, O or S; wherein said alkyl, alkenyl oralkynyl groups in R₄ and R₅ are optionally substituted with Z, each n isindependently 0 to 4; each Z is independently selected from a saturated,partially saturated or unsaturated, monocyclic or bicyclic ring system,wherein each ring comprises 5 to 7 ring atoms independently selectedfrom C, N, O or S; and wherein no more than 4 ring atoms are selectedfrom N, O or S; wherein 1 to 4 hydrogen atoms in Z are optionally andindependently replaced with halo, hydroxy, nitro, cyano, C(O)OH,(C₁-C₃)-straight or branched alkyl, O—(C₁-C₃)-straight or branchedalkyl, C(O)O—[(C₁-C₃)-straight or branched alkyl], amino,NH[(C₁-C₃)-straight or branched alkyl], or N—[(C₁-C₃)-straight orbranched alkyl]₂; J is selected from hydrogen, (C₁-C₆)-straight orbranched alkyl, (C₂-C₆)-straight or branched alkenyl or alkynyl, orcyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenylor alkynyl is optionally and independently replaced with E; K is(C₁-C₁₀)-straight or branched alkyl substituted with phenyl or a(C₂-C₁₀)-straight or branched alkenyl or alkynyl substituted withphenyl; wherein J and K are optionally and independently substitutedwith up to 3 substituents selected from halogen, OH, O—(C₁-C₆)-alkyl,O—(CH₂)n—Z, NO₂, C(O)OH, C(O)—O—(C₁-C₆)-alkyl, C(O)NR⁴R⁵, NR⁴R⁵ and(CH₂)_(n)—Z; G, when present, is —S(O)₂—, —C(O)—, —S(O)₂—Y—, —C(O)—Y—,—C(O)—C(O)—, or —C(O)—C(O)—Y—; Y is oxygen, or N(R⁶); wherein R⁶ ishydrogen, E, (C₁-C₆)-straight or branched alkyl, (C₃-C₆)-straight orbranched alkenyl or alkynyl; or wherein R⁶ and D are taken together withthe atoms to which they are bound to form a 5 to 7 membered ring systemwherein said ring optionally contains 1 to 3 additional heteroatomsindependently selected from O, S, N, NH, SO, or SO₂; and wherein saidring is optionally benzofused; D is a saturated, partially saturated orunsaturated, or aromatic monocyclic or bicyclic ring system, whereineach ring comprises 5 to 7 carbon ring atoms; wherein 1 to 4 hydrogenatoms in D are optionally and independently replaced with halogen,hydroxyl, hydroxymethyl, nitro, SO₃H, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-straight or branched alkyl, (C₂-C₆)-straight or branchedalkenyl, O—[(C₁-C₆)-straight or branched alkyl], O—[(C₃-C₆)-straight orbranched alkenyl], (CH₂)_(n)—N(R⁴)(R⁵), (CH₂)_(n)—NH(R⁴)—(CH₂)_(n)—Z,(CH₂)_(n)—N(R⁴—(CH₂)_(n)—Z)(R⁵—(CH₂)_(n)—Z), (CH₂)_(n)Z, O—(CH₂)_(n)—Z,(CH₂)_(n)—O—Z, S—(CH₂)_(n)—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH,C(O)O—[(C₁-C₆)-straight or branched alkyl], C(O)O—(CH₂)_(n)—Z orC(O)—N(R⁴)(R⁵); m is 0 to 3; and x is 0 or 1; provided that when J ishydrogen or G is selected from S(O)₂—, C(O)C(O)—, SO₂—Y, C(O)—Y, orC(O)C(O)—Y, wherein Y is O; then D is not hydrogen.
 2. The compoundaccording to claim 1, wherein: one of A and B is —CH₂—CH₂-pyridyl or—CH₂—CH₂—CH₂-pyridyl; and the other of A and B is —CH₂—CH₂-phenyl or—CH₂—CH₂—CH₂-phenyl; wherein 1 to 4 hydrogen atoms in said pyridyl orphenyl is optionally and independently replaced with halogen, hydroxyl,hydroxymethyl, nitro, SO₃H, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-straight or branched alkyl, (C₂-C₆)-straight or branchedalkenyl, O—[(C₁-C₆)-straight or branched alkyl], O—[(C₃-C₆)-straight orbranched alkenyl], (CH₂)_(n)—N(R⁴)(R⁵), (CH₂)_(n)—NH(R⁴)—(CH₂)_(n)—Z,(CH₂)_(n)—N(R⁴—(CH₂)_(n)—Z)(R⁵—(CH₂)_(n)—Z), (CH₂)_(n)—Z, O—(CH₂)_(n)—Z,(CH₂)_(n)—O—Z, S—(CH₂)_(n)—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH, orC(O)—N(R⁴)(R⁵)].
 3. The compound according to claim 1 or 2, wherein D isan aromatic monocyclic or bicyclic ring system, wherein each ringcomprises 5 to 7 ring carbon atoms.
 4. The compound according to claim3, wherein: D is phenyl; and x is
 1. 5. The compound according to claim4, wherein G is —C(O)C(O)—.
 6. The compound according to claim 4,wherein G is —SO₂—.
 7. The compound according to claim 4, wherein G is—C(O)—.
 8. The compound according to claim 4, wherein G is —C(O)Y—. 9.The compound according to claim 1 or 2, wherein: x is O; D is phenyl.10. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically effective carrier.
 11. A compoundselected from Table A below: TABLE A

Compd. No. A B R¹ J G 134 phenylpropyl (pyrid-3-yl)-propyl H CH₃ —CH₂—135 phenylpropyl (pyrid-3-yl)-propyl H CH₃ —C(O)— 136 phenylpropyl(pyrid-3-yl)-propyl H CH₃ —C(O)—O—CH₂— 137 phenylpropyl(pyrid-3-yl)-propyl H CH₃ —C(O)—C(O)— 141 phenylpropyl(pyrid-3-yl)-propyl H benzyl —CH₂— 142 phenylpropyl (pyrid-3-yl)-propylH benzyl —C(O)— 143 phenylpropyl (pyrid-3-yl)-propyl H benzyl—C(O)—O—CH₂— 144 phenylpropyl (pyrid-3-yl)-propyl H benzyl —C(O)—C(O)—148 phenylpropyl (pyrid-3-yl)-propyl CH₃ benzyl —CH₂— 149 phenylpropyl(pyrid-3-yl)-propyl CH₃ Benzyl —C(O)— 150 phenylpropyl(pyrid-3-yl)-propyl CH₃ benzyl —C(O)—O—CH₂— 151 phenylpropyl(pyrid-3-yl)-propyl CH₃ Benzyl —C(O)—C(O)— 155 phenylpropyl(pyrid-3-yl)-propyl CH₃ CH₃ —CH₂— 156 phenylpropyl (pyrid-3-yl)-propylCH₃ CH₃ —C(O)— 157 phenylpropyl (pyrid-3-yl)-propyl CH₃ CH₃ —C(O)—O—CH₂—158 phenylpropyl (pyrid-3-yl)-propyl CH₃ CH₃ —C(O)—C(O)—.


12. A pharmaceutical composition according claim 10, comprising acompound according to claim 11 a pharmaceutically acceptable carrier.